Theacrine-based supplement and method of use thereof in a synergistic combination with caffeine

ABSTRACT

A human dietary supplement comprises theacrine and optionally other compounds that modulate the effects of theacrine. Uses for the theacrine-containing supplement include improvement of at least one of mood, energy, focus, concentration or sexual desire or a reduction of at least one of anxiety or fatigue. A synergistic composition comprises co-administration of theacrine and caffeine, wherein the co-administered caffeine reduces theacrine oral clearance (CL/F) and oral volume of distribution (Vd/F). In addition, the co-administered caffeine increases area under the plasma concentration time curve (AUC) of theacrine, and increases theacrine maximum plasma concentration (Cmax) in comparison with the corresponding pharmacokinetic parameters when theacrine is administered alone.

This application is a divisional application claiming the benefit ofU.S. patent application Ser. No. 16/551,373, filed Aug. 26, 2019, whichis a continuation application claiming the benefit of U.S. patentapplication Ser. No. 15/600,371, filed May 19, 2017 and issued as U.S.Pat. No. 10,398,701, which is a continuation-in-part applicationclaiming the benefit of U.S. Ser. No. 14/539,726, filed Nov. 12, 2014and issued as U.S. Pat. No. 10,272,091, which claims the benefit of U.S.Provisional Application Ser. No. 61/903,362, filed Nov. 12, 2013. Eachof the applications identified above is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to systems and methods for utilizingtheacrine alone and in combination for use in providing physiologicalbenefits. More particularly, the invention relates to theacrine andother naturally occurring compounds, whether produced synthetically orharvested from natural sources, and use of these chemical compounds toprovide physiological benefits, which may vary according to theacrineconcentration and the presence of synergists and antagonists.

BACKGROUND OF THE INVENTION

Tea is one of the most widely consumed products in the world. Tea andthe different varieties of tea have been extensively studied. Manyepidemiologic and preclinical studies suggest that drinking tea mayreduce the risk of cancer and cardiovascular disease. Theacrine, analkaloid purine similar to caffeine, is relatively rare and only foundin a few varieties of tea (kucha tea, genus Camellia), the fruitcupuacu, and other plants related to coffee and cacao (genera Coffea andTheobroma), such as Coffea liberica, Coffea dewevrei, Coffea abeokutaeand Theobroma grandiflorum.

1,3,7,9 tetramethyluric acid, commonly known as theacrine, was notstudied until around 1975. However, it has been known of since about1937, when it was detected in dry, decaffeinated Camellia sinensis tealeaves. At this time, the Camellia assamica var. kucha variety of tea isthe primary source of naturally occurring theacrine and produces thechemical in higher concentrations than other known plants.Interestingly, theacrine has not been detected at all in moretraditional teas strains. It is believed to be formed by methylation ofcaffeine and may be an intermediary in the production of liberine orother purines. Its natural function, if any, remains unknown. Theacrinehas garnered attention only relatively recently, and often only as asecondary consideration when analyzing other compounds. Some studiessuggest it may have beneficial qualities, such as serving as aneffective anti-oxidant, anti-inflammatory and may have anti-obesityproperties.

In the studies involving theacrine, beneficial effects may be at leastpartially attributable to an assortment of purine alkaloids and phenoliccompounds. The more common tea-related purine alkaloids includecaffeine, theobromine, theophyline and theacrine. The major tea phenoliccompounds are gallic acid and eight naturally occurring tea catechins,including (+)-catechin (C), (−)-epicatechin (EC), (+)-gallocatechin(GC), (−)-epigallocatechin (EGC), (−)-catechin gallate (CG),(−)-gallocatechin gallate (GCG), (−)-epicatechin gallate (ECG) and(−)-epigallocatechin gallate (EGCG).

Many different biologic and physiologic activities have been attributedto tea and its various components. However, only a few of its componentshave been studied in depth. Caffeine is by far the most studied, and themost commonly used stimulant found in tea. Theacrine appears to have anopposite effect, despite being very similar in chemical structure.Recent experiments have shown that theacrine exhibits a variety ofactivities, some of which seem inconsistent.

In the past several years, there has been a substantial shift in publicopinion toward using naturally occurring chemical compounds for avariety of purposes, instead of synthetic chemicals. For example, a widevariety of natural chemicals are now commonly used as sedatives, e.g.valerian root and chamomile, anti-depressants, e.g. St. John's wort,stimulants, e.g. caffeine, and concentration, e.g. ginseng. In general,naturally occurring compounds may be easier for the body to digest andinteract with and may include minimal and less severe side effects.

It is therefore desirable to identify naturally occurring chemicalcompounds and mixtures thereof that may provide benefits. It is alsodesirable to provide chemical compounds and mixtures thereof that may beused to provide a variety of benefits, varying by concentration, thusrequiring production or harvesting of fewer materials.

SUMMARY OF THE INVENTION

Accordingly, the primary object of the present invention is to provide achemical composition comprising theacrine, either naturally orsynthetically produced, and optionally other chemicals, includingtheacrine congeners or analogs, to provide a plurality of desirableeffects. Theacrine analogs may include, but are not limited to,caffeine, methyl caffeine, theobromine, theophylline, liberine andmethylliberine, and their variants. Other suitable actives may includeone or more ergogenic or nootropic compounds such as CDP choline,alpha-GPC, choline bitartrate, St John's Wort, sulbutiamine, and thelike.

Theacrine exhibits a wide variety of effects depending on dosage. Thepresence of other ingredients may also modulate its effects. It may beused to promote calm or focus and to relax, but also may be used toenhance energy and stamina. It may also serve as an antioxidant and ananti-inflammatory.

In one embodiment, theacrine may be used to modulate stimulants, toprovide heightened energy without heightened anxiety or nervousness.There may be variability among individuals, as described herein.

In another embodiment theacrine may be used as a mild sedative orrelaxant.

In a further embodiment, theacrine may be used to promote weight loss,act as an antioxidant and as an anti-inflammatory. Theacrine may be usedtransdermally to enhance one or more of these effects.

In one embodiment, a dietary supplement comprising about 5 mg to about850 mg theacrine, either natural or synthetic, is provided.

In another embodiment, a method of treatment for improving physicalperformance or energy in an individual is provided. Said method involvesproviding the individual with a composition comprising about 5 mg toabout 850 mg of theacrine, either natural or synthetic, wherein uponadministration of the composition the individual experiences improvementof at least one of mood, energy, focus, concentration or sexual desireor a reduction of at least one of anxiety or fatigue. In anotherembodiment, a second compound such as caffeine may also be administeredin the composition.

It is therefore an object of the present invention to providecompositions including theacrine capable of imparting a plurality ofpositive effects.

It is another object of the present invention to provide congeners,derivatives and iterations of theacrine and synthetic chemicalequivalents of theacrine.

It is another object of the present invention to provide agglomeratedtheacrine, theacrine salts, microencapsulated, liposomal or esterifiedtheacrine.

It is another object of the present invention to provide theacrinecombined with glycerides, propylene glycol, polyethylene glycol (PEG),lauroyl macrogol, lauroyl macrogol derivatives and co-crystallizationproducts of theacrine.

These and other objects and advantages of the present invention willbecome apparent from a reading of the attached specification andappended claims. There has thus been outlined, rather broadly, the moreimportant features of the invention in order that the detaileddescription thereof that follows may be better understood, and in orderthat the present contribution to the art may be better appreciated.There are features of the invention that will be described hereinafterand which will form the subject matter of the claims appended hereto.

In one embodiment, theacrine may be co-administered with caffeine toproduce a synergistic composition, wherein the co-administered caffeinereduces theacrine oral clearance and oral volume of distribution. Theco-administered caffeine in the synergistic composition increases thebioavailability and maximum plasma concentration of theacrine incomparison with the corresponding pharmacokinetic parameters whentheacrine is administered alone.

In one embodiment, a synergistic composition may comprise theacrine andcaffeine having a weight to weight ratio about 1:1.2. Said synergisticcomposition may comprise about 125 mg theacrine and about 150 mgcaffeine. Said synergistic composition may be administered once daily.

In one embodiment, a method of enhancing the intensity and duration oftheacrine' s neurocognitive efficacy beyond a systemic concentrationthreshold. Said method involves providing an individual with asynergistic composition comprising co-administration of theacrine andcaffeine.

In one embodiment, a method of treatment for improving physical ormental performance in an individual is provided. Said method involvesproviding the individual with a synergistic composition comprising about5 mg to about 850 mg of theacrine and about 25 mg to about 650 mg ofcaffeine. Upon administration of the synergistic composition, theindividual experiences improvement of at least one of mood, energy,focus, concentration, cognitive function, or sexual desire or areduction of at least one of anxiety or fatigue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts, in one embodiment, a molecular diagram of theacrine inaccordance with the principles of the invention.

FIG. 2 depicts, in one embodiment, a graph of results of a trial showingperceived energy on a VAS scale (0 to 10 cm) at 1, 2 and 3 hours afteradministration of theacrine or placebo.

FIG. 3 depicts, in one embodiment, a graph of results of a trial showingperceived fatigue on a VAS scale (0 to 10 cm) at 0 minutes and 60minutes after administration of theacrine or placebo.

FIG. 4 depicts, in one embodiment, a graph of results of a trial showingsystolic blood pressure at various time intervals after administrationof theacrine or placebo.

FIG. 5 depicts, in one embodiment, a graph of results of a trial showingdiastolic blood pressure at various time intervals after administrationof theacrine or placebo.

FIG. 6 shows, in one embodiment, the results of a 7 day repeated dosestudy of 200 mg theacrine relative to baseline of fatigue, anxiety andlibido at various intervals after dosages (at 0 hr, 1 hr, 4 hr, 6 hr;bars left to right for each measured category).

FIG. 7 shows, in one embodiment, the results of a 7 day repeated dosestudy of 200 mg theacrine relative to baseline of energy, motivation toexercise, and concentration at various intervals after dosages (at 0 hr,1 hr, 4 hr, 6 hr; bars left to right for each measured category).

FIG. 8(A) depicts, in one embodiment, individual plasma concentrationsof theacrine after single oral dose of theacrine 25 mg.

FIG. 8(B) depicts, in one embodiment, individual plasma concentrationsof theacrine after single oral dose of theacrine 125 mg.

FIG. 8(C) depicts, in one embodiment, individual plasma concentrationsof theacrine after single oral dose of theacrine 125 mg plus caffeine150 mg.

FIG. 9 depicts, in one embodiment, Forest plot illustrating theprobability of interaction magnitude between theacrine and caffeineusing 90% confidence intervals about the geometric mean ratio of theobserved pharmacokinetic parameters following a single theacrine dose(●-25 mg theacrine and ▪-125 mg theacrine in combination with 150 mgcaffeine).

FIG. 10(A) depicts, in one embodiment, individual plasma concentrationsof caffeine after single oral dose of caffeine 150 mg.

FIG. 10(B) depicts, in one embodiment, individual plasma concentrationsof caffeine after single oral dose of theacrine 125 mg plus caffeine 150mg.

FIG. 11 depicts, in one embodiment, Forest plot illustrating theprobability of interaction magnitude between caffeine and theacrineusing 90% confidence intervals about the geometric mean ratio of theobserved pharmacokinetic parameters following a single caffeine dose(150 mg) alone or in combination with theacrine (125 mg).

FIG. 12(A) depicts, in one embodiment, mean values in heart rate aftersingle dose theacrine 25 mg (-●-), theacrine 125 mg (-▪-), caffeine 150mg (-♦-), or theacrine 125 mg plus caffeine 150 mg (-▴-).

FIG. 12(B) depicts, in one embodiment, mean values in systolic bloodpressure after single dose theacrine 25 mg (-●-), theacrine 125 mg(-▪-), caffeine 150 mg (-♦-), or theacrine 125 mg plus caffeine 150 mg(-▴-).

FIG. 12(C) depicts, in one embodiment, mean values in diastolic bloodpressure after single dose theacrine 25 mg (-θ-), theacrine 125 mg(-▪-), caffeine 150 mg (-♦-), or theacrine 125 mg plus caffeine 150 mg(-▴-).

FIG. 12(D) depicts, in one embodiment, mean values in rate pressureproduct after single dose theacrine 25 mg (-●-), theacrine 125 mg (-▪-),caffeine 150 mg (-♦-), or theacrine 125 mg plus caffeine 150 mg (-▴-).

DETAILED DESCRIPTION OF THE INVENTION

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and to the arrangements of the componentsset forth in the following description or illustrated in the drawings.The invention is capable of other embodiments and of being practiced andcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein are for the purpose ofdescription and should not be regarded as limiting.

Disclosed is an invention relating to uses of theacrine, also known as1,3,7,9-tetramethyluric acid, Temurin, Temorine, Tetramethyluric acid,Tetramethyl uric acid and 1,3,7,9-tetramethylpurine-2,6,8-trione.Theacrine may be produced synthetically or may be isolated from anatural source. Theacrine isolated from a natural source may be purifiedto 95% or greater. Optionally, less purification may be used such thattheacrine accounts for 50%, or even less, of the material. In someembodiments, it may be preferable to utilize theacrine isolated from anatural source which may include other congeners of theacrine typicallyfound in theacrine isolates.

In one embodiment, theacrine may be combined with other chemicalcompounds to provide a plurality of positive effects on a human or otheranimal. By altering the dosage of theacrine and/or chemical compounds itis combined with, various physiological effects may be selected for. Thecompositions may provide primarily a single benefit, or may providemultiple benefits simultaneously.

In another embodiment, theacrine may be used at lower dosage levelsand/or in conjunction with compounds that modulate or antagonize itsactivity. Such compositions may induce an improved mood, higher energy,a reduction in fatigue, increased focus, increased concentration,increased mobility, decreased appetite, and increased stamina.

An advantage of using the invention may be the reduced likelihood that aperson develops a tolerance to chemical compositions in accordance withthe principles of the invention. That is, a person may not becomedesensitized to the effects induced.

In another embodiment, theacrine may be used at higher dosage levelsand/or with synergistic compounds. These compositions may increase aperson's basal/resting metabolic rate, increase thermogenesis, decreaseappetite, enhance cognitive performance, increase Alpha wave brainactivity, and/or induce euphoria. Without being bound by theory, theinventors believe that at higher dosage levels, theacrine may benoradrenergic and dopaminergic, and may exhibit increased adenosinereceptor inhibition.

In another embodiment of the invention, theacrine may be combined withephedrine, caffeine, salicylic acid or the like. These may be used toeither modulate the more sedative effects of theacrine or optionally tointeract synergistically with the more stimulating effects of theacrine.For example, theacrine may be combined with caffeine in order tomodulate the excessive stimulatory effects of caffeine, therebystabilizing heart rate and other metabolic activity. That is, acombination of theacrine and caffeine may result in a composition thatimparts the increased focus and energy induced by caffeine, but withoutthe higher heart rate and blood pressure due to modulation of caffeineby theacrine. Thus the combination may result in heightened awarenessand calmness without the jitters caffeine may cause.

Theacrine and caffeine administered in combination has unexpectedeffects. Indeed, it has been unexpectedly found that a combination oftheacrine and caffeine administered to human subjects results inincreased levels of focus, concentration and energy as measured by 100mm VAS scales while also decreasing measures of anxiety, irritability orfeelings of overstimulation. Such decrease in anxiety, irritability,jitters and/or feelings of overstimulation is reflected by patients onstandardized 100 mm VAS at durations of 30 minutes, 60 minutes, 120minutes and 180 minutes as compared with administration of caffeinealone. The combination also exhibits a prolonged duration of action inincreased energy, focus and/or concentration as compared to eithercaffeine or theacrine alone.

Furthermore, theacrine also has unexpected effects on the development oftolerance and habituation of caffeine. In a fourteen day study ofrepetitive dosing of theacrine and caffeine, it was found that thesubjects maintained heightened psychometric indices of energy, focus,concentration, motivation to exercise, motivation to accomplish andfinished tasks, and improved mood at Day 14 as compared to caffeinealone, and absolute levels of energy and motivation were greater thanwith theacrine alone. Those taking theacrine alone still maintainedelevated subjective energy, focus, concentration, motivation toexercise, motivation to accomplish and finish tasks, sexual desire andimproved mood with decreased anxiety as compared to Day 1. Subjectstaking caffeine alone saw decreasing levels of energy, focus andconcentration by Day 5 of the study and had increased anxiety scoresthroughout the study.

In another embodiment of the invention, theacrine may be combined withone or more bioavailability enhancers, including for example bioperine,piperine, black pepper, bergamottin, dihydroxybergamottin (CYP3A4inhibitors), flavonoids (including hesperidin, naringin, tangeritin,quercetin and nobiletin both in isolation and in combination),pterostilbenes, fisetin, nanoencapsulation, microencapsulation,liposomes and/or phytosomes. Which enhancers are combined with theacrinemay depend on which qualities of theacrine are desired for a particularuse.

In another embodiment of the invention, theacrine may be introducedusing one or more delivery methods, including, for example transdermalpatches and/or creams, ready to mix powders, intravenous methods,capsules, tablets, liquid (including liquids for mixing with otherbeverages), softgels, shot format, and/or cosmetic applicationsincluding soaps, lotions and shampoos. Theacrine's anti-inflammatoryqualities may be desired for a variety of topical applications.

In another embodiment of the invention, theacrine may be used to providesports performance enhancers that may reduce fatigue, improve mobility,and improve alertness. In another embodiment of the invention, theacrinemay be used as a topical agent for incorporation into body creams orlotions to produce a cream or lotion for lightening skin, firming skin,and/or improving skin elasticity. A theacrine topical agent may also beused to promote localized transdermal fat loss. Theacrine may also beused in a cream or lotion to promote localized enhanced metabolismand/or enhanced thermogenesis.

In another embodiment of the invention, theacrine may be combined withone or more of an analgesic, for example ibuprofen or salicylic acid,anti-inflammatory agents, salicin, fish oil (omega-3 fatty acids andspecialized, small lipid pro-resolving derivatives), tart cherry, krilloil, astaxanthin, proteolytic enzymes, glucosamine sulfate, chondroitinsulfate, MSM (methyl sulfonylmethane), SAMe (S-adenosylmethionine), ASU(avocado-soybean unsapponifiable fraction), cetyl myristoleate, Dolichosfalcate and/or triterpenoids.

Theacrine itself can reduce biomarkers of inflammation in humans inresponse to acute inflammatory stressors (e.g., intense exercise) orchronic consumption. Theacrine is shown to decrease C-reactive protein(CRP), Erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) andTNF-alpha.

In another embodiment of the invention, theacrine may be combined withextracts from one or more of Acacia catechu, Andrographis paniculata,Scutalleria baicalensis, agmatine sulfate, Stinging Nettle, SeaBuckthorn, curcumin, Cissus Quadrilangularis, Boswellia Serrata, Wasabiajaponica (wasabi extract for Tea Tree Oil), Emu Oil, Arnica, Mangiferaindica L. (Anacardiaceae), Lagenaria breviflora, and/or Zingiberofficinale (ginger & gingerols/shogaols). Such a combination may be usedin, for example, methods of augmenting and enhancing pain modulation,and controlling the inflammatory response.

In another embodiment of the invention, theacrine may be combined withone or more metabolic enhancers including hoodia gordonii, caffeine,yohimbine, synephrine, theobromine, flavonoids, flavanone glycosidessuch as naringin and hesperidin, tocopherols, theophylline,alpha-yohimbine, conjugated linoleic acid (CLA), octopamine, evodiamine,passion flower, red pepper, cayenne, raspberry ketone, guggul, greentea, guarana, kola nut, any beta-phenethylamines, Acacia rigidula,and/or forskolin (Coleus forskohlli). Such a combination may be used in,for example, methods of enhancing 1) thermogenesis/fat and carbohydratemetabolism; 2) fat loss, weight management and improving bodycomposition (loss of body fat, while retaining or sparing lean bodymass/fat free mass/muscle); and/or 3) appetite control/appetitemodulation.

Combinations of theacrine and, for example, caffeine, theobromine, orflavanone glycosides such as naringin or hesperidin, upon administrationto subjects show decreased VAS 100 mm ratings of perceived physicalexertion with exercise as compared to ingredients alone. Theobromine isused by some for improvement of breathing or a subjective feeling ofimproved breathing, but is also known to increase feelings of anxiety,jitters and an elevated heart rate in some subjects. A combination oftheobromine and theacrine retains the beneficial effects while reducingthe unwanted anxiety, jitters and/or elevated heart rate effects.

In another embodiment of the invention, theacrine may be combined withanti-fatigue, focusing and/or energy enhancing ingredients includingcaffeine, theobromine, theophylline, synephrine, yohimbine, rhodiola,ashwagandha, ginseng, ginkgo biloba, siberian ginseng, astragalus,licorice, green tea, reishi, dehydroepiandrosterone (DHEA),pregnenolone, tyrosine, N-acetyl-tyrosine, glucuronolactone, taurine,choline, CDP-choline, alpha-GPC, acetyl-L-carnitine,5-hydroxytryptophan, tryptophan, any beta-phenethylamines, Sceletiumtortuosum (and Mesembrine alkaloids), Dendrobium sp., Acacia rigidula,PQQ (Pyroloquinoline quinone), Ubiquinone(ol) , Nicotinamide riboside,picamilon, Huperzine A (Chinese clubmoss) or Huperzia serrata, L-dopa,Mucuna pruriens, forskolin (Coleus forskohlli). Such a combination maybe used in, for example, methods for enhancing cognitive function,including focus, concentration, sustained attention, working memory,choice and non-choice reaction time, executive function, verbal andnon-verbal learning, visuospatial memory and verbal fluency.

In a further embodiment, theacrine may be combined with a nutritionalcholinergic ingredient such as 2-(dimethylamino)ethanol (DMAE), DMAEbitartrate, choline bitartrate, alpha-GPC(alpha-glycerophosphorylcholine), Huperzine A, CDP choline, orcombinations thereof. One of skill in the art will recognize that theseare merely examples of cholinergic ingredients and that other suchcholinergic ingredients not listed are also contemplated by the presentinvention. The combination of a nutritional cholinergic ingredient withtheacrine can result in a synergistic effect of increased psychometricmeasures for attention, focus and concentration beyond either thetheacrine alone or cholinergic ingredient alone.

In another embodiment, any of the above combinations may be used with anisomer of, congener of, derivative of and/or a metabolite of theacrinesuch as, for example, liberine or methylliberine. Other suitableexamples include methylated theacrine, nitrate salts of theacrine,oxidized theacrine, reduced theacrine and/or theacrine salts.Agglomerated theacrine, microencapsulated theacrine, liposomaltheacrine, esterified theacrine, theacrine glycerides, and mixtures oftheacrine with propylene glycol, lauroyl Macrogol, polyethylene glycol,theacrine derivatives, and/or theacrine co-crystallization products mayalso be used in accordance with the principles of the invention. Suchuse of these, as well as co-crystals or other conjugates (such asquercetin or pterostilbenoids), theacrine salts including citrate,salicylate, malate, tartrate, fumarate, succinate, nitrate, sulfate,phosphate and the like, or PEG-ylated (Macrogol) preparations mayincrease the functional efficacy of the theacrine.

In another embodiment, congeners of theacrine, for example catechins andother flavonoids, may be used an isolated, either independently or incombination with theacrine-based compositions.

The dosage of theacrine may range from about 5 mg to about 850 mg. Inanother embodiment, the range may be from about 65 mg to about 300 mg.In relation to the weight of the human subject, in one embodiment thedosage may be expressed as about 0.75 mg/kg of body weight to about 3mg/kg of body weight. In initial trials the human ED90 appears to beabout 1 mg/kg to about 3 mg/kg.

In one aspect of the invention, the theacrine may be administered withcaffeine. When administered with caffeine, the ratio of caffeine totheacrine, weight to weight, may range from about 0.5:1 to about 50:1,and in another embodiment, from about 1:1 to about 10:1, and in afurther embodiment, from about 2:1 to about 4:1. In administration, thetheacrine may be administered in an amount of about 5 mg to about 800 mgwith caffeine amounts ranging from about 25 mg to about 650 mg. Inanother embodiment the theacrine may be administered in an amount ofabout 5 mg to about 650 mg with the caffeine, and in other embodimentsmay be any amount in that range. Such administration provides anincrease, as measured by 100 mm VAS scales, in at least one of focus,concentration and energy, while also providing a decrease in at leastone of anxiety, irritability, and feelings of overstimulation.Recommended dosages expressed in terms of amount per body weight canrange from about 0.75 mg/kg to about 3 mg/kg of theacrine whenadministered in combination with caffeine, although theacrine may beadministered in the ranges described above up to about 850 mg regardlessof whether it is administered in combination with caffeine.

The invention may be used for the treatment of a variety of conditions,such as improvement of mood, energy, focus, or concentration. Theinvention may also promote a reduced appetite, reduce the perceivedexertion from exercise, decrease the discomfort associated with intenseexercise, and may also improve sexual desire.

EXAMPLES Example 1

In order to examine the beneficial experiential effects and psychometricproperties of theacrine supplementation in healthy subjects, exploreoptimal dosing and potential cumulative effects in a healthy humancohort with a 7-day, sub-acute repetitive dosing protocol, and acquirepreliminary data on various biomarkers of safety and tolerability, anexperiment was performed.

15 healthy subjects (mean±SD age, height, wgt, BMI: 28.3±6.1 y,175.7±11.5 cm, 89.8±21.7 kg, 29.1±4.7) ingested 200 mg of TeaCrine™(Compound Solutions, Inc., Carlsbad, Calif.) (TC) or Placebo (PLA).Anchored VAS questionnaires were used to detect changes in variousaspects of physical and mental energy and performance; side effectprofiles, hemodynamics and biochemical markers of safety were alsocollected over a 3-hr post-dosing period. A subset of 6 subjectsunderwent a separate 7-day, open-label, repeated dose study comparing100 mg, 200 mg and 400 mg of TC.

The experiment was a randomized, placebo-controlled, double-blind,within-subject crossover clinical trial (for N=15 study). A furthersubset study was open-label, sub-acute (7-day), repetitive dosing trial(for N=6 subset).

Six (6) subjects provided written and dated informed consent toparticipate in the 7-day repetitive dosing study between December 15th,2012 and February 21st, 2013. A separate cohort of fifteen (15) subjectsprovided written and dated informed consent for the acute dose,placebo-controlled, crossover clinical trial. All subjects were in goodhealth as determined by physical examination and medical history,between the ages of 18 and 45 (inclusive). Subjects' caffeine intakefrom foods/beverages was limited to <300 mg daily. Subjects were willingand able to comply with the experimental and supplement protocol.

Excluded subjects included subjects who were pregnant or lactating,subjects with a history of hepatorenal, musculoskeletal, autoimmune, orneurologic disease, diabetes, thyroid disease, adrenal disease,hypogonadism, inborn error of metabolism, personal history of heartdisease, high blood pressure (systolic >140 mm Hg & diastolic >90 mmHg), psychiatric disorders, cancer, benign prostate hypertrophy,caffeine sensitivity, gastric ulcer, reflux disease, or any othermedical condition deemed exclusionary by the medical staff, subjectscurrently taking thyroid, hyperlipidemic, hypoglycemic,anti-hypertensive, anti-coagulant medications or OTC products containingpseudoephedrine or other stimulants, subjects who had used anyweight-loss supplements within 30-days prior to the study, subjects whohad gained or lost more than 10 lbs within the past 30 days, subjectswho drank more than one cup of percolated coffee or 2 cups of tea perday, subjects who smoked or had quit smoking within the past six months,subjects who had a known allergy to any of the ingredients in thesupplement or the placebo, and subjects who did not demonstrate a verbalunderstanding of the Informed Consent document.

The study did not incorporate a dietary intervention (other thansupplement/placebo ingestion). Subjects were instructed to complete a24-hr diet record prior to their first laboratory visit, and duplicatethat 24-hr diet prior to each subsequent laboratory visit. The studyalso did not incorporate any physical activity intervention. Subjectsrefrained from exercise and/or heavy physical activity the day prior toeach laboratory visit.

Physical activity levels and health history were determined usingstandardized questionnaires. Heart rate and blood pressure were measuredusing an Omron HEM-780. Standing height was determined using awall-mounted stadiometer. Body weight was measured using a Seca 767™Medical Scale. A 100 mm anchored VAS questionnaire for energy, fatigue,and concentration was distributed at each acute lab session; additionalVAS questionnaires were distributed for the daily assessment over a6-hour period during the 7-day subset study. Quest Diagnostics(Pittsburgh, Pa.) was utilized to transport and analyze all bloodsamples. For each laboratory session, subjects reported to the lab wellhydrated, 10-12 hours postprandial, and at least 24-hours after theirlast exercise session.

Statistical analyses:

Descriptive statistics (mean, median, SD, 95% CIs) were used to quantifysubjects physical characteristics. RM ANOVA, as well analyses ofco-variance (ANCOVA), using baseline scores as the co-variate(respectively), were used to analyze between trial differences. Alphawas set to 0.05 (P≤0.05) for statistical significance, and <0.10 fortrends. Effect sizes were also calculated. Upon arrival for the firsttesting session, subjects were randomly assigned to receive theirrespective supplement/placebo. Each subject ingested the sponsorrecommended dosage of their respective supplement (1 capsule prior toschedule of assessments). Supplements were prepared in capsule form andpackaged in coded generic containers for double-blind administration.

Results:

The 200 mg dose of TC caused significant improvements in energy (TC:+8.6% vs. PLA: −5.7%, P=0.049) and reductions in fatigue (TC: −6.7% vs.PLA: +5.8%, P=0.04). A trend for improved concentration was also noted(TC: +2.4% vs. PLA: −1.3%, P=0.07). No changes in systemic hemodynamicsor side effect profiles were noted. The N=6 cohort study demonstratedmoderate to large effect sizes (0.50 to 0.71) with the 200 mg dose of TCover a 7-day period of assessment for the following subjective measures:energy, fatigue, concentration, anxiety, motivation to exercise andlibido.

The results of the experiment are also shown graphically in FIGS. 2through 7 .

As shown in FIG. 2 , individuals who were administered theacrinereported higher levels of energy at each time increment measured. FIG. 3shows that while individuals given the placebo reported higher fatigueat 60 minutes after administration, those administered theacrinereported lower levels of fatigue. FIGS. 4 and 5 show that no substantialchange in systemic hemodynamics occurred.

FIGS. 6 and 7 show the results of the N=6 cohort study. With a 200 mgdose of theacrine over a 7 day period of assessment, it was observedthat theacrine has a positive effect on each of energy, fatigue,concentration, anxiety, motivation to exercise, and libido. That is,fatigue and anxiety were decreased substantially, while energy,concentration, motivation to exercise and libido were increasedsubstantially.

Thus, the experimental data shows that theacrine supplementation appearsto favorably impact several subjective and psychometric indices ofenergy and fatigue. These findings, as well as the potential cumulativeeffects on focus, concentration, and libido are worthy of future study.

Although previously published animal data suggested much larger doses of“TC” would be necessary to exert its neurophysiological effects, thisfirst-in-human data suggests much lower doses of 1.5 mg to 2.5 mg/kgbodyweight (for example, approximately 200 mg in a 100 kg individual)provide optimal benefit. Follow-up studies should confirm these results,explore other objective measures of physical and cognitive function, andclarify the mechanisms by which theacrine exerts the observed salutaryeffects.

Example 2

Assessment of the Drug-Drug Interaction Potential Between Theacrine AndCaffeine in Humans

Theacrine pharmacokinetics in humans has not been systematicallycharacterized. Therefore, one purpose of this study, among others, wasto determine theacrine pharmacokinetics and dose-linearity followingoral administration in humans. Another purpose of this study is todetermine whether or not caffeine alters theacrine pharmacokineticsand/or pharmacodynamics, when both ingredients are ingested together.

Eight healthy nonsmokers, including 4 men and 4 women, were recruitedfor the experiment. The test subjects regularly consumed stimulants(i.e., caffeine, 50-400 mg/day) with beverages or nutritionalsupplements. The same test subjects did not have a history of adversereactions to caffeine or other stimulants.

Study Design and Procedures

This study was a randomized, double-blind, 4-arm crossover design witheach subject receiving 4 treatments consisting of theacrine (25 mg),theacrine (125 mg), caffeine (150 mg), and theacrine (125 mg) pluscaffeine (150 mg), respectively. Theacrine, administered as iTeaCrine®,was provided by Compound Solutions (Carlsbad, Calif.). Caffeine,administered as caffeine anhydrous, was obtained from NutravativeIngredients (Allen, Tex.). Treatment sequence was randomized using a 4×4Latin square. There was an approximate 1-week washout period betweentreatments for all subjects.

Test Visit Procedures

Each study day, subjects reported to the lab between 6:00 and 7:00 amafter a 10-hour fast and abstinence from beverages, drugs, orsupplements containing alcohol or caffeine (72-hours) and strenuousphysical exercise (24-hours). A catheter was inserted into the forearmvein for blood sampling. Duplicate measurements of resting heart rateand blood pressure were taken pre-dose and prior to each timed bloodsample. In addition, respiratory rate was counted in one minute and bodytemperature was measured using an ear scanning thermometer (dualreadings taken at each time). At approximately 8:00 am, each subjectreceived a single oral dose of a theacrine, caffeine, or combinedtheacrine-caffeine composition accompanied by water. Blood samples at 0minute (5 samples obtained for baseline prior to administration of theoral compositions), 15 minutes, 30 minutes, 60 minutes, and 90 minutes,and 2, 4, 6, 8, and 24 hours post-administration. Collected samples wereprocessed and stored in multiple aliquots (˜500 μL, −70° C.) untilanalyzed for theacrine, caffeine, and paraxanthine using LC-MS/MS.

All subjects were instructed to consume their usual diet throughout thestudy period, with the exception of the actual days of testing. Duringthe two days prior to each test day, subjects recorded all food anddrink consumed and attempted to mimic this intake for the two-day periodprior to subsequent visits. Diet records were analyzed using nutrientanalysis software (Food Processor SQL, version 9.9; ESHA Research,Salem, Oreg.). For the actual test days, standardized meals (mealreplacement food bars [Clif “Builder's 20g Protein Bar”] andready-to-drink shakes [Orgain Organic Nutrition™]) were provided to thesubjects after sample collection at hour 2 and hour 6 (one shake andone-half bar at each time). Subjects were also provided with adequatemeal replacement bars and shakes to consume following the 8 hour samplecollection. (during their time outside the lab). Each bar contained 280calories, 10 grams of fat, 29 grams of carbohydrate, and 20 grams ofprotein. Each shake contained 250 calories, 7 grams of fat, 32 grams ofcarbohydrate, and 16 grams of protein. No food other than what wasprovided to the subjects was allowed during each study day, includingboth time spent in the lab and outside the lab. The only beverage thatthe subjects were allowed to consume was water and the volume consumedwhile in the lab was matched for each test day (men: 94±25 ounces;women: 78±17 ounces). The subjects returned the following morning forthe 24 hour blood collection, again in a 10 hour fasted state. The samevolume of meal replacement bars or shakes was consumed by each subjectduring each visit (both in lab and outside lab). All the subjects exceptone female consumed 3 shakes and 3 bars during the period of timeoutside the lab. Said female subject only consumed 2 bars and 2 shakes.Physical activity remained similar for all the subjects throughout thestudy period, with the exception of refraining from strenuous physicalactivity during the 24-hour period prior to each test day and for theactual test day itself.

Pharmacokinetic Study

Plasma concentration-time data were evaluated using noncompartmentalmethods in Phoenix WinNonlin (version 7.0; Pharsight Corporation,Mountain View, Calif.) with adjustment for lag time after oraladministration. The maximum concentration (C_(max)), lag time (t_(lag)),and time of maximum concentration (t_(max)) were determined from theplasma concentration versus time data. The area under the plasmaconcentration-time curve from time 0 to infinity (was calculated usingthe trapezoidal rule extrapolated to time infinity). The terminalhalf-life (t_(1/2)) was calculated using the following function:t_(1/2)=0.693/k, wherein k is the constant of terminal rate eliminationestimated from the slope of the linear portion of the log plasmaconcentration versus time curve. The oral clearance (CL/F) wascalculated by dividing the oral dose by AUC_(0-∞). The apparent volumeof distribution during the terminal elimination phase (Vz/F) wascalculated by dividing CL/F by k.

Statistical Analysis

Differences between treatment group values were determined for systolicblood pressure (SBP), diastolic blood pressure (DBP), rate pressureproduct, and heart rate. Parametric data were analyzed by pairedStudent's t tests of mean differences in values between treatmentgroups. Statistical significance was defined a priori as a 2-sided or<0.05. The probability of interaction magnitude between theacrine andcaffeine was determined using 90% confidence intervals about thegeometric mean ratio of the observed pharmacokinetic parameters.

Results

Subject characteristics.

Eight physically active and healthy men (n=4; age 34.5±7.0 years; weight94.3±13.1 kg) and women (n=4; age 22.5±3.9 years; weight 66.4±10.1 kg)completed this study. Men ingested a daily amount of caffeine equal to143.8±168.7 mg, while women ingested 144.3±139.7 mg. All the subjectstolerated the treatments well and no adverse events were noted. Dietaryintake was not different across treatment conditions for calories,macronutrients, or micronutrients (p>0.05).

Pharmacokinetics

Mean plasma concentration time profiles for theacrine, caffeine, andparaxanthine are shown in FIGS. 8, 9, and 10 . Theacrine is wellabsorbed following oral administration of theacrine alone reachingmaximal concentration within approximately 2 hours. Dose-adjustedtheacrine pharmacokinetic parameters were not significantly different(Table 1). Theacrine absorption rate (T_(max)) and half-life (t_(1/2))were unaffected by caffeine co-administration. However, caffeineco-administration significantly increased both mean theacrine exposureparameters C_(max), (38.6±16.6 versus 25.6±5.5 ng/mL) and AUC (1.2±1.1versus 0.74±0.31 hr*μg/mL/mg) as well as geometric mean ratios (1.1±0.06and 1.1±0.03) (Table 2). Moreover, caffeine decreased both theacrineoral clearance (CL/F, 1.6±0.49 versus 1.2±0.56 L/hr) and oral volume ofdistribution (Vd/F, 50.5±0.49 versus 35.4±12.4 L) by approximately 30%.Of note, theacrine exposure (AUC) was consistently higher in Subject 8than all other subjects in all treatment arms. However, caffeinepharmacokinetics in Subject 8 was similar to the other seven subjects.Caffeine pharmacokinetics is similar following caffeine alone orcaffeine plus theacrine co-ingestion (FIGS. 10 and 11 and Table 2).Likewise, theacrine co-ingestion did not alter paraxanthine exposureparameters suggesting caffeine metabolism was unaffected by theacrine(Table 3).

TABLE 1 Theacrine Pharmacokinetics Parameter^(a) Condition 1^(b)Condition 2^(c) Condition 4^(d) C_(max) (ng/mL) 34.1 ± 38.9 25.6 ± 5.5 37.7 ± 16.5 T_(max) (hours) 1.8 (0.5-6.0) 1.8 (1.0-4.0) 1.0 (0.3-2.0)t_(1/2) (hours) 16.5 ± 2.4  26.1 ± 13.7 29.2 ± 25.3 AUC (hr*ng/mL/mg)809 ± 923 736 ± 312 1,242 ± 1,129 CL/F (L/hr) 2.0 ± 0.9 1.6 ± 0.5 1.2 ±0.6 Vd/F (L) 48.1 ± 23.4 51.0 ± 8.5  35.4 ± 12.4 MRT (hours) 24.9 ± 3.5 36.8 ± 18.9 41.7 ± 38.8 ^(a)T_(max) values are expressed as median(range). All other values are expressed as mean ± SD and representdose-adjusted pharmacokinetic parameters. ^(b)Theacrine 25 mg^(c)Theacrine 125 mg ^(d)Theacrine 125 mg + Caffeine 150 mg

TABLE 2 Caffeine Pharmacokinetics Parameter^(a) Condition 3^(b)Condition 4^(c) C_(max) (ng/mL) 33.4 ± 9.5  37.4 ± 11.8 T_(max) (hours)0.8 (0.5-1.5) 1.0 (0.3-1.5) t_(1/2) (hours) 6.2 ± 3.8 5.5 ± 2.2 AUC(hr*ng/mL/mg) 262.0 ± 74.1  323 ± 209 CL/F (L/hr) 4.1 ± 1.1 4.3 ± 2.0Vd/F (L) 33.5 ± 13.7 30.2 ± 12.4 MRT (hours) 8.4 ± 4.3 8.0 ± 3.2^(a)T_(max) values are expressed as median (range). All other values areexpressed as mean ± SD and represent dose-adjusted pharmacokineticparameters. ^(b)Caffeine 150 mg ^(c)Theacrine 125 mg + Caffeine 150 mg

TABLE 3 Paraxanthine Pharmacokinetics Parameter^(a) Condition 3^(b)Condition 4^(c) C_(max) (ng/mL) 7.3 ± 1.5 8.4 ± 3.5 T_(max) (hours) 5.0(4.0-8.0) 7.0 (1.5-8.0) t_(1/2) (hours) 12.5 ± 12.7 14.8 ± 17.7 AUC(hr*ng/mL/mg) 174 ± 152 209 ± 202 MRT (hours) 19.1 ± 18.6 22.7 ± 26.2^(a)T_(max) values are expressed as median (range). All other values areexpressed as mean ± SD and represent dose-adjusted pharmacokineticparameters. ^(b)Caffeine 150 mg ^(c)Theacrine 125 mg + Caffeine 150 mg

Pharmacodynamics

Hemodynamic parameters such as blood pressure and heart rate areelevated following co-administration of caffeine and other stimulantssuch as ephedrine. To determine the potential for a pharmacodynamicsinteraction between theacrine and caffeine, we evaluated systolic anddiastolic blood pressure, heart rate, and rate pressure productfollowing administration of both theacrine (25 mg and 125 mg) andcaffeine (150 mg) alone and in combination (theacrine 125 mg pluscaffeine 150 mg). Heart rate decreased slightly over the first two hoursfollowing administration for each of the four conditions returning tobaseline by 24 hours post-ingestion (FIG. 12A). Systolic/diastolic bloodpressure and rate pressure product remained relatively constant acrossthe 24 hour evaluation period for each of the four conditions (FIGS.12B, 12C, and 12D).

The experimental results reveal that the pharmacokinetics of theacrine,when ingested alone, were similar between the two doses tested. However,following co-ingestion with caffeine, theacrine disposition wassignificantly altered. Specifically, caffeine decreased theacrine's oralclearance (CL/F), which correlated with enhanced theacrine exposureparameters, area under the plasma concentration time curve (AUC) andmaximum concentration (C_(max)). It is impossible to determine withcertainty the exact mechanism for enhanced theacrine exposure, viz.,decreased CL and/or increased oral bioavailability (F), in the absenceof intravenous data. However, the finding that theacrine's eliminationhalf-life (t_(1/2) or Vd/CL) was unaffected by caffeine indicates thatcaffeine enhances theacrine's oral bioavailability (F), which is alsoconsistent with the decreased oral volume of distribution (Vd/F) oftheacrine. Theacrine had no impact on the pharmacokinetics of caffeineor paraxanthine, which is the primary caffeine metabolite in humansformed via CYP1A2-mediated 3-N-demethylation. Caffeine is completelyabsorbed following oral administration. Such results indicate thattheacrine would not have a reciprocal effect on caffeinebioavailability. Determination of whether or not theacrine is a CYP1A2substrate will provide further insight into caffeine's effect ontheacrine disposition, viz., enhanced fraction absorbed and/or reducedfirst-pass hepatic metabolism.

One study subject was found to have exaggerated theacrine exposure inall treatment arms. It is unclear, however, whether the finding isgenetic and/or environmental. The presence of a 5-methyl substituent anda carbamide at the 6-position distinguish theacrine from caffeine.Because theacrine contains a 3-methyl substituent, the primary site ofcaffeine metabolism via CYP1A2-mediated demethylation, it is possiblethat theacrine is also susceptible to CYP1A2-mediated metabolism.Caffeine exposure (AUC_(0-∞)) is controlled by both environmental, aswell as genetic factors. In particular, the CYP1A2 polymorphism(r52470893), located in the common promoter region between CYPJA] andCYP1A2, significantly associated with caffeine exposure in non-smokers,but not in smokers. Non-smokers heterozygous or homozygous for theCYPJAI/CYP1A2 A allele had a significantly lower caffeine exposurecompared to nullizygous individuals. Additional environmental factorsincluding oral contraceptive use mask the effect of genetics on caffeinemetabolism. The role of pharmacogenetics in theacrine pharmacokineticsand pharmacodynamics is of potential importance should CYP1A2 prove tobe an important theacrine elimination pathway.

At the doses tested, the results reveal no effect on baselinehemodynamic parameters, e.g. heart rate and blood pressure, among thesubjects receiving theacrine or caffeine administered alone or incombination. Such data are consistent with other studies demonstratingthat theacrine supplementation (up to 400 mg/day for 8 weeks) appears tobe safe in humans with no adverse effects on hemodynamic parameters. Itis surprised to find that in repeat dose theacrine studies there is anabsence of either sensitization or pharmacodynamic tolerance. Caffeineis a mixed A₁/A₂, adenosine receptor (AR) antagonist. It is believedthat the acute psychostimulatory activity of caffeine is related to itsability to antagonize the A₁ AR, which removes inhibition of the A_(2A)AR leading to NMDA-dependent release of glutamate and dopamine.Following chronic caffeine administration, however, caffeine's primaryeffects shift from A₁-dependent to A_(2A)-dependent antagonism intolerant individuals due to A₁ AR desensitization. Administration of acocktail containing both A₁ and A_(2A) AR antagonists blocks theacrinestimulating activity in rats. However, simultaneous administration of A₁and A_(2A) AR antagonists prevents the determination of individualcontribution of A₁ and A_(2A) AR to the pharmacologic effects oftheacrine. These data present a hypothesis that theacrine has differentA₁ and A_(2A) binding affinities than caffeine, which permitsdiscrimination between the A1 and A_(2A) receptors at physiologicallyrelevant concentrations. Theacrine's preferential reliance on A_(2A) ARantagonism would provide a mechanistic basis for lack of pharmacodynamictolerance. Overall, the experimental data suggest that the interactionsbetween theacrine and adenosine receptors are complex.

Example 3 Improvements in Subjective Feelings, Cognitive Performance,and Hemodynamics

In one clinical study, the effects of a single dose of theacrine,caffeine, or their combination on subjective feelings, cognitiveperformance, and hemodynamics in men and women were examined. In thestudy, 24 men and 26 women ingested a placebo, theacrine at 25 mg,theacrine at 125 mg, caffeine at 150 mg, or combination of 125 mgtheacrine and 150 mg caffeine on five separate occasions, which wereseparated by approximately one week. Subjects rated their subjectivefeelings using a 10 cm visual analog scale at 30 minutes, 1, 2, 3, 4,and 5 hours post ingestion and performed the trail making test (TMT) ofcognitive performance at baseline and at hours 2 and 4 post ingestion.Subjective feelings of attentiveness, sense of focus, and sense ofenergy improved with all active treatments. More favorable scores weregenerally associated with the caffeine and theacrine/caffeinecombination treatments. Self-reported motivation to exercisesignificantly increased in caffeine and theacrine/caffeine combinationtreatments. Caffeine and theacrine/caffeine combination resulted in asignificant increase in subjective focus from baseline to 2 hourspost-ingestion, while the 125 mg theacrine treatment reached statisticalsignificance at 3 hours post-ingestion. Motivation to exercise and senseof energy significantly increased from baseline to 2 hourspost-ingestion in caffeine and theacrine/caffeine combinationtreatments. No condition effects were noted for the TMT (p>0.05),although a trend was present (p=0.069) for theacrine/caffeinecombination treatment, with TMT time improved at 4 hours post ingestioncompared to pre-ingestion. These findings indicate that theacrine, whenused alone at 125 mg or in combination with caffeine, is safe andeffective at improving subjective feelings related to energy in healthymen and women. Moreover, the data show that the combination of theacrineand caffeine may improve cognitive performance as assessed by the TMT.

Example 4 Improvements in Cognitive Performance

Another clinical study will demonstrate synergistic improvements inexercise performance and time to exhaustion obtained from 125 mgtheacrine and 150 mg caffeine combination treatment over 275 mg caffeineor 275 theacrine administered alone. The purpose of this randomized,placebo-controlled, four-condition, double-blind clinical trial is todetermine and compare the effects of theacrine to caffeine on variousmeasures of cognitive performance under fatiguing conditions of asimulated athletic contest in high level male and female soccer players.Secondary purposes are to determine whether there is a synergisticeffect of theacrine/caffeine combination as well as the impact ontime-to-exhaustion in an “added time” scenario. After giving informedconsent, 20 (males n=10, females n=10) Division I and professionalsoccer players will undergo baseline performance testing and thenrandomly assigned to order of supplementation of a placebo (P), caffeine(C), theacrine (T), and theacrine/caffeine combination (TC). In eachcondition, subjects will undergo a 15 minutes dynamic warm-up and thenengage in a simulated soccer game on a high-speed treadmill. The “game”will be divided into two 45-minute halves. Simple, choice, andcognitive-load reaction time will be assessed immediately following each45-minute half. After the second assessment, subjects will immediatelybe put back on the treadmill and asked to run to volitional fatigue at90% VO2max. The experimental results indicated that 125 mg theacrine/150mg caffeine combined treatment outperformed 275 mg pure caffeine or 275mg pure theacrine interventions. At almost half of the pure caffeine orpure theacrine dose, the combined theacrine/caffeine treatment resultedin a true synergistic and superior performance in comparison to the purecaffeine, the pure theacrine, or placebo group. More specifically, thecombination of 125 mg theacrine/150 mg caffeine outperformed all othergroups, including 275 mg pure caffeine, 275 mg of pure theacrine, andplacebo, in measures of cognitive flexibility, attention and taskswitching, complex-choice reaction time and information processing.

Routes of Administration

The compounds may be administered by any route, including but notlimited to oral, sublingual, buccal, ocular, pulmonary, rectal, andparenteral administration, or as an oral or nasal spray (e.g. inhalationof nebulized vapors, droplets, or solid particles). Parenteraladministration includes, for example, intravenous, intramuscular,intraarterial, intraperitoneal, intranasal, intravaginal, intravesical(e.g., to the bladder), intradermal, transdermal, topical, orsubcutaneous administration. Also contemplated within the scope of theinvention is the instillation of theacrine in the body of the patient ina controlled formulation, with systemic or local release of the drug tooccur at a later time. For example, the drug may be localized in a depotfor controlled release to the circulation.

The pharmaceutical compositions of the present invention may beadministered in combination with a pharmaceutically acceptable carrier.The active ingredients in such formulations may comprise from 1% byweight to 99% by weight, or alternatively, 0.1% by weight to 99.9% byweight. “Pharmaceutically acceptable carrier” means any carrier, diluentor excipient that is compatible with the other ingredients of theformulation and not deleterious to the user. Useful excipients includemicrocrystalline cellulose, magnesium stearate, calcium stearate, anyacceptable sugar (e.g., mannitol, xylitol), and for cosmetic use anoil-base is preferred.

The nutraceutical compositions of the present invention may beadministered in combination with a nutraceutically acceptable carrier.The active ingredients in such formulations may comprise from 1% byweight to 99% by weight, or alternatively, 0.1% by weight to 99.9% byweight. “Nutraceutically acceptable carrier” means any carrier, diluentor excipient that is compatible with the other ingredients of theformulation and not deleterious to the user. Useful excipients includemicrocrystalline cellulose, magnesium stearate, calcium stearate, anyacceptable sugar (e.g., mannitol, xylitol), and for cosmetic use anoil-base is preferred.

Whereas, the present invention has been described in relation to certainembodiments thereof, and many details have been put forth in itsillustration, it should be understood that other and furthermodifications, apart from those shown or suggested herein, may be madewithin the spirit and scope of this invention. Descriptions of theembodiments shown in the drawings should not be construed as limiting ordefining the ordinary and plain meanings of the terms of the claimsunless such is explicitly indicated.

As such, those skilled in the art will appreciate that the conception,upon which this disclosure is based, may readily be utilized as a basisfor the designing of other structures, methods and system for carryingout the several purposes of the present invention. It is important,therefore, that the claims be regarded as including such equivalentconstructions insofar as they do not depart from the spirit and scope ofthe present invention.

All references cited herein are incorporated by reference in theirentirety. The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims, ratherthan to the foregoing specification, as indicating the scope of theinvention.

We claim:
 1. A method of formulating a dietary supplement comprising thestep of: combining a nutraceutically acceptable carrier with theacrine,caffeine, and methylliberine; wherein the dietary supplement isformulated for oral administration; wherein the theacrine is present inthe dietary supplement in an amount that is to modulate activity of thecaffeine; and wherein the theacrine and caffeine are present in thedietary supplement in a ratio of about 0.5:1 to about 50:1 by weightcaffeine:theacrine.
 2. The method of claim 1, wherein the theacrine hasa purity of at least 95%.
 3. The method of claim 1, wherein thetheacrine is present in the dietary supplement in an amount of fromabout 5 mg to about 850 mg.
 4. The method of claim 1, wherein thedietary supplement is formulated into a solid oral dosage form.
 5. Themethod of claim 4, wherein said solid oral dosage form is a powder,capsule, or tablet.
 6. The method of claim 1, wherein the dietarysupplement is formulated to, upon oral administration, increase mood,energy, focus, concentration, and/or sexual desire. 7 The method ofclaim 1, wherein the theacrine is produced synthetically or is isolatedfrom a natural source and purified to at least 50% theacrine.
 8. Themethod of claim 1, wherein said caffeine is present in the dietarysupplement in an amount of about 25 mg to about 650 mg.
 9. The method ofclaim 1, wherein the theacrine is present in the dietary supplement inan amount from about 65 mg to about 300 mg.
 10. The method of claim 1,wherein the ratio is about 1:1 to about 10:1.
 11. The method of claim 1,wherein the ratio is about 2:1 to about 4:1.
 12. The method of claim 1,wherein the ratio is about 1.2:1.
 13. A method of modulating activity ofa stimulant comprising the steps of: providing a dietary supplementcomprising a nutraceutically acceptable carrier in combination withtheacrine, caffeine, and methylliberine, and administering the dietarysupplement to a subject to modulate activity of the stimulant; whereinthe dietary supplement is formulated for oral administration; whereinthe stimulant is caffeine, and theacrine is included in the supplementin an amount that modulates activity of the caffeine; wherein thetheacrine and caffeine are present in the dietary supplement in a ratioof about 0.5:1 to about 50:1 by weight caffeine:theacrine.
 14. Themethod of claim 13, wherein the theacrine has a purity of at least 95%.15. The method of claim 13, wherein the theacrine is present in thedietary supplement in an amount of from about 5 mg to about 850 mg. 16.The method of claim 13, wherein the dietary supplement is formulatedinto a solid oral dosage form.
 17. The method of claim 16, wherein saidsolid oral dosage form is a powder, capsule, or tablet.
 18. The methodof claim 13, wherein the dietary supplement is formulated to, upon oraladministration, increase mood, energy, focus, concentration, and/orsexual desire.
 19. The method of claim 13, wherein the theacrine isproduced synthetically or is isolated from a natural source and purifiedto at least 50% theacrine.
 20. The method of claim 13, wherein saidcaffeine is present in the dietary supplement in an amount of about 25mg to about 650 mg.
 21. The method of claim 13, wherein the theacrine ispresent in the dietary supplement in an amount from about 65 mg to about300 mg.
 22. The method of claim 13, wherein the ratio is about 1:1 toabout 10:1.
 23. The method of claim 13, wherein the ratio is about 2:1to about 4:1.
 24. The method of claim 13, wherein the ratio is about1.2:1.